Obesity and hypertension (HTN) have additive effects in increasing the risk for cardiovascular disease, a leading cause of death in the developed world. Obese individuals commonly have HTN, and obesity appears to be an important cause of treatment-resistant HTN. Oxidative stress and impaired renal Na excretion are strongly associated with obesity induced HTN. Nevertheless, it is not completely known how oxidative stress affects renal Na handling and blood pressure (BP). We have demonstrated a novel mechanism by which Na/K- ATPase, serving as an amplifier for reactive oxygen species, regulates renal proximal tubular (PT) Na transport and then blood pressure through Na/K-ATPase signaling. Pilot studies have shown that protein carbonylation, a widely accepted marker for oxidative stress, is pervasive in renal PT Na/K-ATPase in hypertensive and obese mice. Thus, the central hypothesis of this proposal is that obesity is complicated by chronic oxidant stress within the kidney. This leads to pervasive carbonylation of the proximal tubular Na/K-ATPase ?1 subunit which impairs proximal tubular Na/K-ATPase-Src-ROS signal transduction and ion transporter redistribution. As a result, animals with such chronic oxidant stress have impaired natriuresis in response to increases in dietary Na and become hypertensive. We will test this hypothesis through both in vitro and in vivo studies. In Aim 1, we will investigate the effect of chronic oxidative stress induced by glucose oxidase on Na/K- ATPase-mediated renal PT Na transport. In Aim 2, we will use diet induced C57BL/6 obese mice and polygenic obese TALLYHO/JngJ mice for covering a broader spectrum of human disease mechanisms. We will test the effect of chronic oxidative stress induced by obesity on Na/K-ATPase signaling-mediated renal Na handling and BP as well as effect of the specific Na/K-ATPase signaling antagonist, pNaKtide, on this process. The novel findings of this study may allow for the identification of new targets for interventions in the clinical treatment of obesity related hypertension. Finally, as COBRE junior investigator I will receive scientific and career mentoring while generating important novel preliminary data to apply for NIH R01 funding to become an independent investigator.